Pf4 Pharmacophores and Their Uses

A compound that modulates PF4 activity comprising functional groups I, II, III, IV, VIII, IX and X wherein the distance between the functional groups in three-dimensions is about:

• 2.25±0.05 Å between groups I and II;
• 6.03±1.37 Å between groups I and III;
• 6.92±1.60 Å between groups I and IV;
• 8.57±2.60 Å between groups I and VIII;
• 14.20±1.53 Å between groups I and IX;
• 12.54±1.51 Å between groups I and X;
• 6.00±2.43 Å between groups II and III;
• 7.01±1.84 Å between groups II and IV;
• 9.09±1.22 Å between groups II and VIII;
• 14.45±0.24 Å between groups II and IX;
• 13.28±0.37 Å between groups II and X;
• 2.31±0.07 Å between groups III and IV;
• 9.19±1.40 Å between groups III and VIII;
• 10.91±1.74 Å between groups III and IX;
• 7.06±2.49 Å between groups III and X;
• 9.02±0.63 Å between groups IV and VIII;
• 10.46±0.46 Å between groups IV and IX;
• 6.52±1.26 Å between groups IV and X;
• 6.87±0.96 Å between groups VIII and IX
• 9.84±1.05 Å between groups VIII and X;
• and
• 7.25±0.49 Å between groups 1× and X
• wherein functional group I corresponds to the OD1 atom of the amino acid side chain Asp7, functional group II corresponds to the OD2 atom of the amino acid side chain Asp7, functional group III corresponds to the NE2 atom of the amino acid side chain Gln9, functional group IV corresponds to the OE1 atom of the amino acid side chain Gln9, functional group VIII corresponds to the CG atom of the amino acid side chain Leu8, and functional group X corresponds to the CG atom of the amino acid side chain Leu11 in the PF4 sequence set forth in FIG. 1C (SEQ ID NO:1), and
• wherein said compound is not PF4, IL-8, a PF4 Mutant or a peptide having the amino acid sequence selected from the group consisting of SEQ ID NOS:34-154.

A method for identifying a compound that modulates PF4 activity, which method comprises comparing:

• (a) a three-dimensional structure of a candidate compound, to
• (b) a three-dimensional structure of a PF4 pharmacophore,
• wherein said PF4 pharmacophore comprises functional groups I, II, III, IV, VIII, IX and X
• wherein the distance between the functional groups in three-dimensions is about:
• 2.25±0.05 Å between groups I and II;
• 6.03±1.37 Å between groups I and III;
• 6.92±1.60 Å between groups I and IV;
• 8.57±2.60 Å between groups I and VIII;
• 14.20±1.53 Å between groups I and IX;
• 12.54±1.51 Å between groups I and X;
• 6.00±2.43 Å between groups II and III;
• 7.01±1.84 Å between groups II and IV;
• 9.09±1.22 Å between groups II and VIII
• 14.45±0.24 Å between groups II and IX;
• 13.28±0.37 Å between groups II and X;
• 2.31±0.07 Å between groups III and IV;
• 9.19±1.40 Å between groups III and VIII
• 10.91±1.74 Å between groups III and IX;
• 7.06±2.49 Å between groups III and X;
• 9.02±0.63 Å between groups IV and VIII;
• 10.46±0.46 Å between groups IV and IX;
• 6.52±1.26 Å between groups IV and X;
• 6.87±0.96 Å between groups VIII and IX
• 9.84±1.05 Å between groups VIII and X;
• and
• 7.25±0.49 Å between groups 1× and X
• wherein functional group I corresponds to the OD1 atom of the amino acid side chain Asp7, functional group II corresponds to the OD2 atom of the amino acid side chain Asp7, functional group III corresponds to the NE2 atom of the amino acid side chain Gln9, functional group IV corresponds to the OE1 atom of the amino acid side chain Gln9, functional group VIII corresponds to the CG atom of the amino acid side chain Leu8, and functional group X corresponds to the CG atom of the amino acid side chain Leu11 in the PF4 sequence set forth in FIG. 1C (SEQ ID NO:1),
• wherein said candidate compound is not PF4, IL-8, a PF4 Mutant or a peptide having the amino acid sequence selected from the group consisting of SEQ ID NOS:34-156;
• and
• wherein similarity between the three-dimensional structures of the candidate compound and the PF4 pharmacophore is indicative of the candidate compound's ability to modulate PF4 activity.